Mer, Tyro and Axl are members of the TAM subfamily of receptor tyrosine kinases (RTK). FLT3 belongs to type Ⅲ RTKs. Containing an extracellular domain for ligand binding and intracellular kinase domains that mediate autophosphorylation, recruitment of downstream signaling molecules, and signal transduction, RTKs are mediators of cellular proliferation.
UNC2025 is a Mer and FLT3 dual inhibitor. The inhibitory IC50s of UNC2025 against Mer and FLT3 kinase were 0.8 nM and 0.74 nM, respectively, and the Kis were 0.16 nM and 0.59 nM, respectively. In B-ALL 697 cells, UNC2025 inhibited Mer phosphorylation with an IC50 of 2.7 nM and in Molm-14 cells, UNC2025 decreased FLT3 phosphorylation with an IC50 of 14 nM. UNC2025 dose-dependently inhibited colony formation of A549 cells at the concentrations of 50, 100, and 300 nM, and that of Molm-14 cells at the concentrations of 10, 25, and 50 nM[3]. 72h treatment of 300 nM UNC2025 induced apoptosis in NSCLC H2228, A549, Colo699 and H1299 cells[4].
In NSG mice transplanted with B-ALL cells by i.v. injection, a single dose of UNC2025 (3 mg/kg) administrated orally was sufficient to decrease Merphospho-protein levels in bone marrow leukemia cells by greater than 90%[3]. In H2228 or A549 xenografts established in nude mice, UNC2025 administrated at the dose of 50 mg/kg twice daily by oral gavage reduced tumor volume by 70.2% and 61.9%, respectively[4].
作用机制
UNC2025 inhibited Mer and FLT3 kinase activity in an ATP competitive manner.
UNC2025 细胞实验
Cell Line
Concentration
Treated Time
Description
References
G361
1000 nM
90 minutes
inhibition of MERTK activation and downstream signaling
Mol Cancer Ther. 2019 Feb;18(2):278-288.
J774
134 nM
5 days
Evaluate the inhibitory effect of UNC2025 on J774 cell growth, with an IC50 of 134 nM.
Neuro Oncol. 2018 Jan 10;20(1):92-102.
EOC 2
199 nM
5 days
Evaluate the inhibitory effect of UNC2025 on EOC 2 cell growth, with an IC50 of 199 nM.
Neuro Oncol. 2018 Jan 10;20(1):92-102.
GSC20
1.5 µM
5 days
Evaluate the inhibitory effect of UNC2025 on GSC20 cell growth, with an IC50 of 1.5 µM.
Neuro Oncol. 2018 Jan 10;20(1):92-102.
GSC11
86 nM
5 days
Evaluate the inhibitory effect of UNC2025 on GSC11 cell growth, with an IC50 of 86 nM.
Neuro Oncol. 2018 Jan 10;20(1):92-102.
MeWo
100 nM
72 hours
reduction in survivin levels
Mol Cancer Ther. 2019 Feb;18(2):278-288.
A101D
50 nM
10 days
reduction in colony formation
Mol Cancer Ther. 2019 Feb;18(2):278-288.
HMCB
300 nM
90 minutes
inhibition of MERTK activation and downstream signaling
Mol Cancer Ther. 2019 Feb;18(2):278-288.
TRP
231.6 nM
5 days
Evaluate the inhibitory effect of UNC2025 on TRP cell growth, with an IC50 of 231.6 nM.
Neuro Oncol. 2018 Jan 10;20(1):92-102.
AML-123009 patient sample
25-300nM
48 hours
Inhibited colony formation, >90% inhibition at 300nM
Clin Cancer Res. 2017 Mar 15;23(6):1481-1492.
NOMO-1 AML cells
200-300nM
48 hours
Induced cell death, 25-90% of cells died after 48-hour treatment
Clin Cancer Res. 2017 Mar 15;23(6):1481-1492.
Jurkat T-ALL cells
200-300nM
48 hours
Induced cell death, 25-90% of cells died after 48-hour treatment
Clin Cancer Res. 2017 Mar 15;23(6):1481-1492.
Kasumi-1 AML cells
200-300nM
48 hours
Induced cell death, 25-90% of cells died after 48-hour treatment
Clin Cancer Res. 2017 Mar 15;23(6):1481-1492.
697 B-ALL cells
200-300nM
48 hours
Induced cell death, 25-90% of cells died after 48-hour treatment
Clin Cancer Res. 2017 Mar 15;23(6):1481-1492.
M2 macrophages
1 µg/mL
2 hours
Inhibit MerTK phosphorylation and block efferocytosis of apoptotic cells
Nat Commun. 2023 Mar 25;14(1):1675.
Schwannoma cells
0.03-6.0 μM
72 hours and 7 days
UNC2025 decreased the total number of schwannoma cells, increased the number of dead cells, and reduced the proliferation of Ki67-positive cells.
Oncogene. 2024 Oct;43(41):3049-3061.
Meningioma cells
0.03-6.0 μM
72 hours and 7 days
UNC2025 decreased the total number of meningioma cells, increased the number of dead cells, and reduced the proliferation of Ki67-positive cells.
To evaluate the effect of UNC2025 on meningioma spheroid viability, results showed UNC2025 significantly decreased spheroid viability.
Acta Neuropathol Commun. 2023 Dec 15;11(1):198.
H1299
300 nM
72 hours
To assess the effect of UNC2025 on apoptosis, results showed UNC2025 significantly increased apoptosis.
Mol Cancer Ther. 2015 Sep;14(9):2014-22.
Colo699
300 nM
72 hours
To assess the effect of UNC2025 on apoptosis, results showed UNC2025 significantly increased apoptosis.
Mol Cancer Ther. 2015 Sep;14(9):2014-22.
A549
300 nM
72 hours
To assess the effect of UNC2025 on apoptosis, results showed UNC2025 significantly increased apoptosis.
Mol Cancer Ther. 2015 Sep;14(9):2014-22.
H2228
300 nM
72 hours
To assess the effect of UNC2025 on apoptosis, results showed UNC2025 significantly increased apoptosis.
Mol Cancer Ther. 2015 Sep;14(9):2014-22.
UNC2025 动物实验
Species
Animal Model
Administration
Dosage
Frequency
Description
References
NOD/SCID/gamma mice
Human leukemia xenograft model
Oral
3 mg/kg
Single dose, bone marrow cells collected 30 minutes later
To evaluate the inhibitory effect of UNC2025 on Mer phosphorylation in vivo, results showed significant reduction in Mer phospho-protein levels
J Med Chem. 2014 Aug 28;57(16):7031-41.
Nude mice
Subcutaneous xenograft model
Oral gavage
30 mg/kg or 50 mg/kg
Twice daily for several weeks
To assess the effect of UNC2025 on tumor growth, results showed UNC2025 significantly inhibited tumor growth.
Mol Cancer Ther. 2015 Sep;14(9):2014-22.
Mice
TRP allograft model
Oral gavage
65 mg/kg
Once daily starting from day 7
Evaluate the effect of UNC2025 alone or in combination with radiotherapy on the survival of TRP allograft model mice. Results showed that UNC2025 alone did not significantly prolong survival, but when combined with radiotherapy, 19.4% of mice survived more than 60 days, with complete tumor regression in some mice.
Neuro Oncol. 2018 Jan 10;20(1):92-102.
Nude mice
MHH-ES-1 xenograft model
Intraperitoneal injection
10 mg/kg
Every 3 days for 28 days
UNC2025 enhanced irinotecan's suppression of tumor growth
Nat Commun. 2024 Jun 21;15(1):5292.
NSG mice
697 B-ALL xenograft model
Oral
50-75mg/kg
Once daily, continuous treatment
Significantly reduced tumor burden, median survival increased from 26 days to 70 days
Clin Cancer Res. 2017 Mar 15;23(6):1481-1492.
C57BL/6 mice
B16F10 melanoma model
Peritumoral injection
2.7 µg/mouse
Every 3 days for two times
Inhibit tumor growth and metastasis, enhance antitumor immune responses
Nat Commun. 2023 Mar 25;14(1):1675.
Mice
FeCl3-Induced Carotid Artery Thrombosis model
Intravenous injection
3 mg/kg
Single dose, circulated for 30 minutes
Prolonged time to initial clot formation and decreased thrombus stability
J Thromb Haemost. 2018 Feb;16(2):352-363.
Male C57BL/6 mice
Hepatic ischemia-reperfusion injury model
Intravenous injection
50 mg/kg
Single dose, followed by reperfusion for up to 6 or 24 hours
UNC2025 significantly inhibited MSC-EVs-induced phagocytosis of apoptotic cells by macrophages and increased liver injury
Inhibition of EGFR extracellular/transmembrane domain-tagged Mer intracellular domain (unknown origin) expressed in 32D cells assessed as inhibition EGF-stimulated of phosphorylation pretreated for 1 hr prior to EGF stimulation by Western blot analysis, IC50=2.7 nM
25068800
697 cells
Function assay
1 h
Inhibition of Mer phosphorylation in human 697 cells preincubated for 1 hr by densitometry, IC50=2.7 nM
25068800
A549 cells
50-300 nM
Function assay
Inhibition of Mer-mediated colony formation in human A549 cells at 50 to 300 nM measured after 2 weeks by soft agar colony formation assay
25068800
Molm-14 cells
Function assay
1 h
Inhibition of Flt3 phosphorylation in human Molm-14 cells preincubated for 1 hr by densitometry, IC50=0.014 μM
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